Recommendations for the Optimal Care of Patients with Recent-Onset

Ofﬁ cial journal of the bs_bs_banner Paciﬁ c Rim College of Psychiatrists

Asia-Pacific Psychiatry ISSN 1758-5864

GUIDELINES Recommendations for the optimal care of patients with recent-onset psychosis in the Asia-Pacific region Tak Lam Lo 1 MBBS, MRCPsych, FHKCPsy, FHKAM (Psychiatry), Matthew Warden2 MBBS, MRCP Psych, Dip Mental Health Law, Yanling He3 MD, Tianmei Si4 MD, PhD, Seshadri Kalyanasundaram5 MBBS, MD, Manickam Thirunavukarasu6 MD (Psy), DPM, Nurmiati Amir7 MD, Ahmad Hatim8 PhD, MBBS, Tomas Bautista9 MD, FPPA, Cheng Lee10 MBBS, MMed (Psychiatry), Robin Emsley11 MBChB, MMed (Psych), FCPsych (SA), MD, DSc, Jose Olivares12 MD, PhD, Yen Kuang Yang13 MD, Ronnachai Kongsakon14 MD, MRCPsy, LLB, MSc & David Castle15 MBChB, MSc, GCUT, DLSHTM, MD

1 Kwai Chung Hospital, Kowloon, Hong Kong 2 Hobart and Southern CMHT, Tasmanian Health Organisation – South, Tasmania, Australia 3 Department of Epidemiology Shanghai Mental Health Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China 4 Department of Psychopharmacology, Peking University Institute of Mental Health, Peking, China 5 Hon. CEO, Richmond Fellowship Society, Bangalore, India 6 Department of Psychiatry SRM University, Kattankulathur, India 7 Department of Psychiatry National General Hospital, Ciptomangunkusumo/Faculty of Medicine, University of Indonesia, Jakarta, Indonesia 8 Department of Psychological Medicine, University of Malaya, Kuala Lumpur, Malaya 9 College of Medicine Philippine General Hospital, University of the Philippines, Manila, Philippines 10 Department of Community Psychiatry, Institute of Mental Health, Singapore 11 Department of Psychiatry, University of Stellenbosch, Stellenbosch, South Africa 12 Department of Psychiatry, Complejo Hospitalario Universitario de Vigo, Vigo, Spain 13 Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 14 Department of Psychiatry, Ramathibodi Hospital, Bangkok, Thailand 15 Department of Psychiatry, St. Vincent’s Hospital, The University of Melbourne, Melbourne, Australia

Keywords Abstract adherence, evidence-based practice, expert Providing optimal care to patients with recent-onset psychosis can consensus, first-episode, schizophrenia improve outcomes and reduce relapse. However, there is a lack of con- Correspondence sistency of the implementation of guidelines for such patients across the Tak Lam Lo MBBS, MRCPsych, FHKCPsy, FHKAM Asia-Pacific region. We determined a pragmatic set of recommendations (Psychiatry), 3-15 Kwai Chung Hospital Road, for use on a day-to-day basis to help provide optimal care at this crucial Kowloon, Hong Kong. stage of illness. The recommendations were developed over a series of Tel: +852 2959 8002 meetings by an international faculty of 15 experts from the Asia-Pacific Fax: +852 2959 8399 region, Europe, and South Africa. A structured search of the PubMed Email: [email protected] database was conducted. This was further developed based on the faculty’s clinical experience and knowledge of the literature into 10 key Received 6 May 2015 aspects of optimal care for patients during the first five years of a diag- Accepted 29 December 2015 nosis of a psychotic disorder, with particular relevance to the Asia-Pacific DOI:10.1111/appy.12234 region. Several common principles emerged: adherence to antipsychotic medications is crucial; substance abuse, psychiatric and medical comorbidities should be addressed; psychosocial interventions play a pivotal role; and family members can play a vital role in overall patient care. By following these recommendations, clinicians may improve outcomes for patients with recent-onset psychosis.

Introduction and functional beneﬁts (Andreasen et al., 2013). Also, longer duration of untreated psychosis (DUP) is asso- Evidence is emerging that relapse prevention after the ciated with worse long-term outcome (Tang et al., initial onset of psychosis may confer signiﬁcant clinical 2014). For example, Fraguas et al. (2014) reported

154 Asia-Pacific Psychiatry 8 (2016) 154–171 © 2016 TheAuthorsAsia-PacificPsychiatryPublishedbyJohn Wiley & Sons Australia, Ltd ThisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercial-NoDerivsLicense,whichpermitsuseanddistributioninanymedium, providedtheoriginalworkisproperlycited,theuseisnon-commercialandnomodificationsoradaptationsaremade. T.L. Lo et al. Optimal care of recent-onset psychosis

longer DUP to be associated with a lower Children’s Methods Global Assessment of Functioning (C-GAF) score at two years, less improvement in C-GAF, and An international group of 15 clinicians from the A-P lower rates of clinical remission in early-onset psycho- region, Europe and South Africa (Australia [DC, MW]; sis. There is also evidence that brain-derived mainland China [YH, TS]; Hong Kong [TLL]; India neurotrophic factor (BDNF) levels are negatively cor- [SK, MT]; Indonesia [NA]; Malaysia [AH]; Philippines related with DUP and may reflect both an acute [TB]; Singapore [CL]; South Africa [RE]; Spain [JO]; neurodegenerative reaction during the untreated Taiwan [YKY], and Thailand [RK]) with extensive phase of psychosis (Rizos et al., 2010); and develop- experience of treating patients with schizophrenia and ment of psychosis has itself been associated with an interest in recent-onset psychosis convened to progressive structural brain changes around the time propose a concise set of principles aimed at helping of onset (Ziermans et al., 2012). Thus, prompt initia- psychiatrists within the A-P region to provide optimal tion of antipsychotic medication is a vital component care to recent-onset psychosis patients. of optimal care early in the course of psychosis. Of A structured literature search was conducted particular importance is medication adherence focusing on the impact of adherence, as this was con- as non-adherence to antipsychotic medication has a sidered one of the key influences on treatment out- significant negative impact on treatment response comes on recent-onset psychosis. The search of (Lindenmayer et al., 2009). Poor adherence leads to an PubMed used the following search terms: (schizophre- increase in hospitalization rates (Ascher-Svanum nia OR schizophrenic OR psychosis OR psychotic) et al., 2006; Novick et al., 2010), impaired functioning AND (first episode OR FEP OR first-episode OR early (Ascher-Svanum et al., 2006), and an increased risk psychosis OR early onset OR early illness OR treat- of relapse (Novick et al., 2010). Problems with adher- ment naive) AND (adherence OR adherent OR adhere ence are particularly common during the early stages OR compliance OR comply OR discontinuation OR of schizophrenia, with as many as 59% of patients discontinue) limited to English language articles pub- becoming partially adherent or non-adherent lished between 1 January 2007 and 1 April 2014. within 12 months of their first psychotic episode Initially, 400 abstracts were identified and subse- (Coldham et al., 2002). Non-adherence to anti- quently reviewed by a medical writer against the psychotic medication during the first year following search criteria. Of these, 216 were retained for abstract diagnosis is a significant predictor of poorer outcomes review by the core group of clinicians (TLL, RE, JO, in the subsequent two years (Ascher-Svanum et al., DC). Ultimately, 137 full articles were selected and 2006) and the biggest predictive factor of reviewed to evaluate the level of evidence and identify relapse after a first episode of psychosis (Caseiro et al., key themes. 2012). Articles previously highlighted for rejection at These findings highlight the importance of pro- full article review stage were also reassessed (see viding optimal care in a timely fashion to patients in Figure 1). the early stages of their disease. There is compelling In addition, based on their clinical experience and literature on optimal care in recent-onset psychosis; knowledge of the literature, the core group considered however, these guidelines may not have been uni- that a number of additional aspects beyond treatment formly adopted in the Asia-Pacific (A-P) region. adherence were relevant in providing optimal care Therefore, there is a need to evaluate the available and outcomes for patients with recent-onset psycho- evidence and identify the key aspects of optimal sis. They delineated nine proposed themes for consid- care for patients during recent-onset psychosis eration and discussion with the wider group of which are applicable in the A-P region. The A-P clinicians. The wider group revised the proposed region is extremely diverse with different health themes and reached agreement on 10 aspects of care care systems, levels of socioeconomic development that should be the focus for delivering optimal benefits and cultural attitudes, and we recognize that it is for patients following the first five years of a diagnosis not possible to provide that same level of treatment of psychosis with a particular focus on their feasibility throughout the region. To this end, we aimed to and applicability in the diverse settings of the A-P evaluate the recent evidence relating to the first region. At this stage, an additional 94 articles were five years of a diagnosis of psychosis and reach con- included and 89 of the original full articles were dis- sensus about general principles of care that could carded, leaving a total of 142 articles. The 10 themes become expected clinical practice across the A-P and our recommendations are shown in Table 1. The region. rationale for their inclusion is discussed below.

Figure 1. Structured literature search. FEP, first episode psychosis.

Results For example, Filipino psychiatrists always seek actively to engage with, and seek the help of, the Theme 1: Strategic engagement of patients with patient’s family, especially to provide an understand- recent-onset psychosis is important to the ing of the nature of the illness. Family members are success of subsequent care trained to assist patients with recovering psychosocial functions and play a key role with medication adher- Poor therapeutic alliance predicts poor service engage- ence. Due to the stigma associated with schizophrenia, ment (Lecomte et al., 2008) and poor adherence peer group interventions are unpopular and patients (Tunis et al., 2007; Montreuil et al., 2012) in recent- and families seek to keep the illness a private, family onset psychosis. In turn, the severity of positive symp- matter wherever possible (Bautista T, 2015 personal toms, agreeableness as a personality trait, and poor communication). capacity in building an alliance, all have a negative Treating positive symptoms with a reactive admission- impact on treatment adherence and service engage- based approach and little or no follow-up is a sub-optimal ment (Lecomte et al., 2008). The patient’s decision to approach. It is not enough to manage an episode of psychosis stay with treatment is dependent upon relationships as an isolated event. Once a patient is discharged, ongoing between clinicians who embrace patient-centered per- continuity of community care, together with consistency spectives and peers who have also experienced first- within the treatment team, where possible, are crucial. This episode psychosis (FEP) (Stewart, 2013). A critical approach will facilitate a deeper level of engagement with the time for engagement is the transition between initial patient and their family and a greater understanding of the treatment and community care (Tiihonen et al., 2011). patient’s individual needs and broader issues, thereby assist- Success of this transition is marked by patient contact ing with the selection of optimum interventions to promote with patient-centered care providers and a supportive continued recovery. This theme reflects a need for willingness, peer group. Patient-centered early intervention staff is on the part of patients, health care professionals (HCPs) and important for engagement (Stewart, 2013). families, to engage in continuous and monitored treatment Patients have different needs based on their age, and acknowledges the importance of a combined approach education, and support systems; older first-episode that includes both family members and HCPs. patients tend to have an increase in metabolic and mood disorder comorbidity, and a longer DUP (Selvendra et al., 2014). Patients who are older at Theme 2: Effective symptom control in recent-onset psychosis can usually be achieved initial diagnosis often achieve better outcomes than with antipsychotics younger patients (Rabinowitz et al., 2006). Within the A-P region, the patient’s family plays a Patterns of prescribing differ widely across the A-P particularly important role in many aspects of care. region. The Health Insurance Review & Assessment

Table 1. Themes and recommendations

Theme Recommendation 1. Strategic engagement of Treating positive symptoms with a reactive admission-based approach and little or no follow-up is a suboptimal patients with recent-onset approach. It is not enough to manage an episode of psychosis as an isolated event. Once a patient is psychosis is important to discharged, ongoing continuity of community care, together with consistency within the treatment team, the success of subsequent where possible, are crucial. This approach will facilitate a deeper level of engagement with the patient and their care family and a greater understanding of the patient’s individual needs and broader issues, thereby assisting with the selection of optimum interventions to promote continued recovery. This theme reflects a need for willingness, on the part of patients, HCPs and families, to engage in continuous and monitored treatment and acknowledges the importance of a combined approach that includes both family members and HCPs. 2. Effective symptom control While we acknowledge that the availability, cost, and reimbursement status of different antipsychotics varies in recent-onset psychosis throughout the A-P region, patients and their families should be informed of the pharmacological treatment can usually be achieved options available to them including possible AEs. with antipsychotics 3. Restoring psychosocial Remission and recovery are achievable for many patients providing they are well informed, adequately treated, function in recent-onset and closely monitored. The expectations of patients and their caregivers should be taken into account when psychosis is an essential evaluating remission and recovery, together with a realistic and culturally sensitive outlook provided by the component in recovery HCP. 4. Medication adherence is Adherence to medication is crucial in preventing relapse and improving outcomes in schizophrenia. Patients a critical contributor to should be warned of the dangers of stopping their medication and that they may be required to keep taking relapse reduction in medication despite improvement in their symptoms. Care should be taken by HCPs when conveying this recent-onset psychosis information as poor timing and/or bad phrasing can reduce the patient’s willingness to comply. Interventions that directly improve adherence behavior, especially those that target substance abuse and depressive symptoms, should be developed. Measures to improve patient insight could be a specific target of treatment in early intervention programs. 5. Long-acting injectable While we acknowledge that there is a need for a large-scale, randomized controlled trial comparing oral and LAI antipsychotics should be APs in recent-onset psychosis, to assess long-term outcomes, we believe LAI APs may play a role in relapse considered in recent-onset prevention via increased rates of adherence and should be considered as an early stage treatment. LAI APs are schizophrenia frequently perceived by patients and family members as an indication that the patient has a severe mental illness and are therefore reluctant to use them. However, many first-episode patients respond well to LAI APs and, once provided with balanced information, are open to their use. 6. Psychosocial A number of culturally adapted psychosocial therapies are now available throughout the A-P region. Psychosocial interventions contribute therapies, together with continuous antipsychotic therapy, facilitate recovery and improve adherence to much to desirable clinical treatment, thereby offering significant benefits to recent-onset patients in social and vocational aspects. outcomes in recent-onset Psychosocial therapies should be implemented early to prevent deterioration of psychosocial and cognitive psychosis functions. 7. Involvement of families As already highlighted in themes 1, 2, and 6, family members and carers play an important role in supporting and carers is an integral patients with medication adherence and day-to-day tasks. Stigma may prevent patients and family members part of comprehensive seeking help during the early stages of the disease and beyond. Efforts should be made to reduce stigmatizing patient management in behavior within health care services and society as a whole particularly in countries where there is strong recent-onset psychosis stigma attached to mental illness. The sociocultural context is important to take into account in discussions with family members. 8. Substance abuse in Comorbid substance abuse can worsen symptoms and outcomes and is a growing problem in the A-P region, recent-onset psychosis despite the variability in the rates and types of substances abused. The negative contribution that illicit drugs impacts negatively on and alcohol make to the course of the illness, not least the legal complications, including a heightened risk of outcomes and needs to be incarceration should be emphasized early in the treatment pathway. Patients should be offered interventions addressed that address comorbid substance abuse in a culturally sensitive manner. 9. Psychiatric comorbidities Psychiatric comorbidities such as depression and anxiety disorders can have a negative impact on outcomes. We are common and should be recommend that psychiatric comorbidities be given high priority during treatment planning in the context of addressed in recent-onset the socioeconomic and cultural background. psychosis 10. Medical comorbidities are Psychiatrists should be conscious of the physical conditions and metabolic issues associated with the use of common and should be antipsychotic drugs and the potential for antipsychotic therapies to worsen existing conditions such as monitored and addressed diabetes and compromised lipid metabolism. Strategies to improve health and well-being should be promoted fastidiously in recent-onset early on, and all patients should be screened regularly for metabolic abnormalities. psychosis

AE, adverse event; A-P, Asia-Pacific; HCP, healthcare professional; LAI AP, long-acting injectable antipsychotic.

Service-National Patients Sample was a stratified sam- Some long-term studies of FEP have found no pling from the entire population under the South difference between individual SGAs in clinical Korean national health security system in 2009 and functional outcomes, (Shrivastava et al., 2012) (Park et al., 2014). The 26,254 patients who were pre- whereas others demonstrate benefits for particular scribed first-generation antipsychotics (FGAs) only SGAs. For instance, olanzapine might lead to longer were significantly older, more likely to be male and on treatment continuation in treatment-naive FEP Medicaid, had higher total medical costs and lower patients than haloperidol and, possibly, ziprasidone rates of self-payment, and higher co-medication rates (San et al., 2012). What is clear is that appropriate of anti-Parkinsonian agents and anxiolytics than antipsychotic options are available to address symp- the 67,361 patients prescribed second-generation toms in recent-onset psychosis (Schimmelmann et al., antipsychotics (SGAs) only (Park et al., 2014). Japan 2007; Gafoor et al., 2010). has a high frequency of polypharmacy (Kishimoto Clozapine has a high maintenance rate (Noguera et al., 2013b). Singapore has a high utilization of depot et al., 2013), and may have a marginally superior effi- injections (Chong et al., 2004). Owing to the availabil- cacy in the initial year of treatment of treatment-naive ity of inexpensive generics, clozapine has been exten- FEP patients, which can be explained for the most part sively used in China for the treatment of resistant by greater adherence (Sanz-Fuentenebro et al., 2013). and non-resistant schizophrenia for longer than in Guidelines recommend that clozapine should be con- any other East Asian country (Chong et al., 2004). sidered as a third-line treatment as it leads to earlier Haloperidol is the most commonly prescribed and longer remission intervals (Remington et al., antipsychotic in Malaysia and a third of patients are 2013); however, identification of true refractoriness prescribed SGAs, with olanzapine the most common should be made as early as possible and clozapine (Yoon and Aziz, 2014). Strict regulations for the use of considered earlier rather than later. Antipsychotics are SGAs, including clozapine, have been implemented in effective treatments in FEP at doses lower than those other countries, making it difficult to prescribe these used in patients with long-term schizophrenia (Gafoor drugs; however, there has been an increase in their et al., 2010; Zhang et al., 2013a) though they may be use in recent years (Shinfuku and Tan, 2008; Tan et al., associated with a relatively higher incidence of 2008). adverse effects (AEs) such as tardive dyskinesia Positive symptoms are more readily addressed by (Zhang et al., 2013a). antipsychotic treatments and the negative and cogni- Current (UK) National Institute for Health and tive symptoms which often remain are a considerable Care Excellence (NICE) guidelines recommend the impairment for patients (Citrome, 2014). Meta- integration of pharmacological and psychosocial treat- analysis of the efficacy and tolerability of FGAs versus ments for optimal long-term outcomes for patients SGAs in FEP shows that, when pooled, SGAs are with schizophrenia (NICE, 2014). Long-acting inject- similar to FGAs regarding total psychopathology able antipsychotics (LAI APs) should be considered for change, depression, treatment response, and meta- patients with recurrent relapses related to partial/non- bolic changes (Zhang et al., 2013a). SGAs significantly adherence. The oral form of the same medication is outperformed FGAs regarding lower treatment the logical choice for initial treatment (APA, 2004; discontinuation (irrespective of cause), negative Lehman et al., 2004). symptoms and global cognition; and were associated Whilst we acknowledge that the availability, cost and with fewer extrapyramidal symptoms and akathisia. reimbursement status of different antipsychotics varies In contrast, SGAs tended to be associated with more throughout the A-P region, patients and their families should weight gain (P < 0.05–0.01) (Zhang et al., 2013a). A be informed of the pharmacological treatment options avail- meta-analysis of the relapse rates associated with able to them including possible AEs. FGAs versus SGAs failed to demonstrate a consistent superiority of individual SGAs over FGAs. Neverthe- less, SGAs as a group were associated with less study- Theme 3: Restoring psychosocial function in recent-onset psychosis is an essential defined relapse, overall treatment failure and component in recovery hospitalization, than FGAs, with a modest but clinically relevant effect size (Kishimoto et al., 2013a). Improvements in patient functioning have a consider- Meta-analysis of mid- to long-term outcomes associ- able impact on patients’ lives, which in turn will ated with SGAs showed efficacy not only during the improve quality of life and reduce carer burden acute phase but, more importantly, as maintenance (Durmaz and Okanlı, 2014). Remission is significantly treatments (Glick et al., 2011). associated with adherence, and outcome is significantly

associated with good adherence to medication partially or non-adherent to medication, while only (Bachmann et al., 2008; Hassan and Taha, 2011). While 32% of patients related clinical deterioration to there has been some discussion around remission being antipsychotic non-adherence (Olivares et al., 2013). able to be achieved with low dose or intermittent Patients’ insight and treatment adherence significantly treatment (Wunderink et al., 2007, 2013), there is con- predict the clinical course and functional outcome in sistent evidence that relapse rates are high following FEP (Steger et al., 2012). A better attitude toward discontinuation regardless of the preceding period of antipsychotic medication at the first lifetime psychiat- stabilization (Subotnik et al., 2011; Emsley et al., 2012, ric admission is significantly related to lower all-cause 2013; Zipursky et al., 2014). Relapse, following antipsychotic treatment discontinuation following a discontinuation, frequently occurs with little warning first early-onset psychotic episode (Fraguas et al., (Gaebel and Riesbeck, 2014) and once illness recurs, 2008). There are complex and often overlapping symptom severity rapidly returns to previous levels. factors that influence non-adherence. Ongoing sub- Furthermore, treatment nonresponse may emerge in a stance abuse/dependence (Tunis et al., 2007; Perkins subset of patients after relapse (Emsley et al., 2013). et al., 2008) and depressive symptoms (Perkins et al., Long-term remission can be achieved in FEP 2008) are associated with poor adherence and are patients for a relatively long follow-up period (Üçok significant predictors of treatment discontinuation. et al., 2011; Morgan et al., 2014). Strategies to reduce Non-adherence early after discharge is associated with DUP and achieve early response could improve remis- a higher risk or hospitalization (Bodén et al., 2011); sion rates in FEP patients (Verma et al., 2012). Both however, adherence and outcome are similar irrespec- negative symptoms (Austin et al., 2013) and neuro- tive of whether a patient’s first hospitalization was cognitive deficits (Fervaha et al., 2014) play a central involuntary or voluntary (Opjordsmoen et al., 2010). role in the process of recovery from schizophrenia. Medication costs have also been associated with poor Remission of symptoms alone is no longer consid- adherence especially in developing countries such as ered sufficient and recovery is about a broader set of India (Shoib et al., 2014) and Pakistan (Tharani et al., psychosocial outcomes (Andreasen et al., 2005). The 2013). physician’s view of recovery (e.g. maintaining a job in A poor treatment response may cause some a supermarket) does not always match with family/ patients to stop medications prematurely (Perkins carer’s views, where there is often an expectation that et al., 2008), while others may become non-adherent recovery will be reflected in a return to the pre-disease if their symptoms improve – presumably because they state (Siu et al., 2012). Such views might be impacted believe that they no longer require treatment (Steger by social role expectations that vary across the A-P et al., 2012). Of these, FEP patients who experience a region. For instance, mental health nurses in Thailand rapid reduction of negative symptoms are at particu- (Kaewprom et al., 2011) tend to view recovery as larly high risk of non-adherence and should be closely symptomatic remission rather than the emerging, monitored (Steger et al., 2012). There is also a sub- consumer-based concept of personal recovery (Tse group of patients who refuse medication altogether; a et al., 2014). Rates of functional recovery are lower medical file audit of 605 FEP patients revealed that than those of symptomatic remission (Menezes et al., almost 20% were persistent medication refusers 2009; Henry et al., 2010). Nevertheless, patients (Lambert et al., 2010). In this group, poor premorbid enrolled in specialized early intervention programs functioning, comorbid substance use, poor insight, can achieve both social/vocational recovery and forensic history, and a lack of previous contact with symptomatic remission (Henry et al., 2010). psychiatric care predicted medication refusal (Lambert Remission and recovery are achievable for many et al., 2010). patients providing they are well informed, adequately Relapse rates in the three years following the first treated, and closely monitored. The expectations of patients psychotic episode are high at around 50% (Gearing and their caregivers should be taken into account when et al., 2009; Hui et al., 2013). Non-adherence to medi- evaluating remission and recovery. cation is highly predictive of relapse (Gearing et al., 2009; Novick et al., 2010; Alvarez-Jimenez et al., 2012; Caseiro et al., 2012; Hui et al., 2013) and even brief Theme 4: Medication adherence is a critical periods of partial non-adherence (2–4 weeks) lead to a contributor to relapse reduction in greater risk of relapse (Subotnik et al., 2011). Relapse recent-onset psychosis prevention after the initial onset of schizophrenia may In a recent survey, 56% of patients with psychosis in convey a significant clinical benefit (Andreasen et al., the A-P region were judged by their psychiatrists to be 2013). Therefore, strategies to enhance treatment

adherence, as a way of preventing relapse, should be option for addressing adherence problems, compared implemented at the time of illness onset. This is espe- with three in five psychiatrists practicing in Europe cially important since early warning signs of relapse (Olivares et al., 2013). A survey conducted in 2004 in are often unreliable (Gaebel and Riesbeck, 2014) and East Asia showed that LAI APs were prescribed in “rescue” medication may prove ineffective in prevent- 15.3% (368/2399) of patients, rates were highest ing a full-blown psychotic recurrence (Emsley et al., in Singapore (75.0%), followed by Taiwan (20.3%), 2013). Japan (6.2%), mainland China (5.9%), and Hong Adherence to medication is crucial in preventing relapse Kong (4.7%) (Sim et al., 2004). The current prescrip- and improving outcomes in schizophrenia. Patients should be tion rate of LAI APs is less than 1% in South Korea warned of the dangers of stopping their medication and that which may reflect negative attitudes, inexperience, or they may be required to keep taking medication despite reluctance of psychiatrists rather than patient resis- improvement in their symptoms. Care should be taken by tance (Kim et al., 2013). HCPs when conveying this information as poor timing While we acknowledge that there is a need for a large- and/or bad phrasing can reduce the patient’s willingness to scale, randomized controlled trial comparing oral and LAI comply. Interventions that directly improve adherence behav- APs in recent-onset psychosis, to assess long-term outcomes, ior, especially those that target substance abuse and depres- we believe LAI APs may play a role in relapse prevention sive symptoms, should be developed. Measures to improve via increased rates of adherence and should be considered patient insight could be a specific target of treatment in early as an early-stage treatment. LAI APs are frequently per- intervention programs. ceived by patients and family members as an indication that the patient has a severe mental illness and are therefore reluctant to use them. However, many first-episode Theme 5: Long-acting injectable antipsychotics patients respond well to LAI APs and, once provided with should be considered in recent-onset balanced information, are open to their use. schizophrenia Despite their potential advantages, most treatment guidelines advise limiting the use of LAI APs to Theme 6: Psychosocial interventions contribute much to desirable clinical outcomes in multiple-episode or non-adherent patients, with con- recent-onset psychosis troversy in relation to their role in early schizophrenia (Kim et al., 2012); however, recommendations for LAI Community psychosocial interventions for schizo- AP use early in the disease course are emerging, not phrenia have been found to be effective in reducing least during the first two to five years following diag- positive and negative symptoms and general psycho- nosis (Malla et al., 2013) and as maintenance treat- pathology, both after the first psychotic episode and at ment following the initial episode (Llorca et al., 2013). other stages of the illness (Armijo et al., 2013). Both Using LAI APs as the initial therapeutic treatment can long-term psychosocial therapies (Zaytseva et al., reduce relapse rates and improve prognosis (Viala 2010) and peer support initiatives (Boardman et al., et al., 2012), and many first-episode patients taking 2014) can be effective in improving medication adher- oral antipsychotics will accept a recommendation of ence. Specific adherence coping education therapy is the corresponding LAI therapy (Weiden et al., 2009). well accepted and associated with significant decreases Recent-onset psychosis patients receiving LAIs show in symptoms, as well as trend-level improvements in more symptom reduction and better health-related attitudes toward treatment (Uzenoff et al., 2008). Cog- quality of life and functional outcomes (Emsley et al., nitive Behavioral Therapy (CBT) is widely accepted 2008) as well as significantly lower 1- and 2-year as an effective intervention for the treatment of FEP relapse rates than patients receiving oral therapy (Kim (Fanning et al., 2012). However, when CBT is avail- et al., 2008). LAI APs may be useful in the treatment of able as part of a package of phase-specific interven- recent-onset psychosis in terms of symptom control tions within an early intervention service, it appears and relapse reduction, particularly if chosen by the that individuals who have fewer years in education patient or when medication adherence is a priority and more negative symptoms are less likely to engage (Taylor and Ng, 2013). However, in a recent survey, with and complete the treatment (Fanning et al., only one in three psychiatrists from mainland China, 2012). A longer DUP and a low level of insight also India, Australia, Taiwan, Vietnam, New Zealand, Indo- predict poor adherence to CBT (Alvarez-Jiménez et al., nesia, Hong Kong, the Philippines, Thailand, Singa- 2009). Treatment in specially designed early detection pore, Malaysia, and South Korea favored switching to and intervention centers may improve functioning or adding an LAI AP as their preferred treatment of people with an early initial prodromal state of

psychosis, and although both CBT and supportive Theme 7: Involvement of families and carers is counseling (SC) led to significant social adjustment an integral part of comprehensive patient improvements, CBT was not superior to SC at the end management in recent-onset psychosis of treatment (Bechdolf et al., 2007). CBT has been In recent years, the responsibility of care has seen a culturally adapted for low and middle-income coun- global shift in emphasis from the hospital setting to tries and has been effective in reducing psychopathol- patients’ families (Gutiérrez-Maldonado et al., 2005; ogy and improving insight in Pakistani patients Awad and Voruganti, 2008). Families have tradition- (Naeem et al., 2015). Phase-specific early psychosocial ally been the mainstay of care for the mentally ill in interventions in Hong Kong have been shown to sub- the A-P region (Chakrabarti, 2011), and the move stantially reduce hospitalization and symptoms (Chen toward greater deinstitutionalization has resulted et al., 2012). in about 70% of East Asian patients with schizophre- Meta-analysis shows that interventions that nia being cared for in the community by their include families are more effective in reducing symp- families (Chan, 2011). Recent initiatives including toms by the end of treatment and preventing relapse psychoeducational programs involving family at 7–12 month follow-up (Lincoln et al., 2007). Fur- members improve relapse rates (Lincoln et al., 2007). thermore, young people and their parents are more Within the A-P region, case management and likely to endorse informal social supports, generic mutual support groups involving family members counseling, and general stress reduction methods than have been shown to reduce symptoms and improve taking antipsychotic medication, using mental health functioning in patients in mainland China, Hong services, or the helpfulness of seeing a psychiatrist Kong, and Australia (in both English and Vietnamese (Jorm et al., 2008). Interventions involving family speaking families) (Bradley et al., 2006; Chien and members have been shown to improve outcomes in Wong, 2007; Chien and Chan, 2013; Chien and mainland China, Hong Kong, and Australia (in both Thompson, 2013; Chen et al., 2014). English and Vietnamese families (Bradley et al., 2006; However, non-professional carers of patients with Chien and Wong, 2007; Chien and Chan, 2013; Chien schizophrenia experience a considerable level of and Thompson, 2013; Chen et al., 2014). burden due to the significant demands imposed by the Interventions of a purely educational nature are condition, which impacts detrimentally on their the least successful at improving antipsychotic adher- quality of life. In 1937, the Japanese Society of Psy- ence, and the greatest improvements are seen with chiatry and Neurology approved the translation of interventions employing combinations of educa- the term schizophrenia as “seishin-bunretsu-byo” tional, behavioral, and affective (designed to optimize (Chinese pronunciation “jing-shen-fen-lie-zheng,” social and emotional support) strategies (Dolder et al., Korean pronunciation “jungshinbunyeolbyung”). The 2003). Combination strategies also reduce relapse, Japanese Society of Psychiatry and Neurology decrease hospitalization, decrease psychopathology, replaced the old term with “togo-shitcho-sho (integra- improve social function, provide gains in medication tion disorder)” in 2002 at the request of the National knowledge, and improve insight into the need for Federation of Families of the mentally ill in Japan treatment. Longer interventions and a good thera- (Sato, 2008). In Hong Kong, the term “si-jue-shi-diao” peutic alliance are also important for successful out- (dysregulation of thought and perception), which comes (Dolder et al., 2003). Vocational programs, means psychosis, has been used instead of “jing-shen- especially the individual placement and support bing” in an effort to make psychiatric services more model, are effective in schizophrenia and have been accessible to young people with psychosis (Chung and validated in many different cultures (Mueser and Chan, 2004). Taiwan uses the term “si-jue-shi-diao” McGurk, 2014) including in Hong Kong (Kin Wong (Sartorius et al., 2014). In 2011, the Korean Neuro- et al., 2008), Australia (Killackey et al., 2008), and psychiatric Association and the Korean Society of Japan (Sato et al., 2013). Schizophrenia Research replaced the old term with A number of culturally adapted psychosocial therapies “johyeonbyung” (metaphorically describing schizo- are now available throughout the A-P region. Psychosocial phrenia as a disease of inadequate tuning of the neural therapies, together with continuous antipsychotic therapy, network or the mind) following a South Korean Inter- facilitate recovery and improve adherence to treatment, net schizophrenia advocacy group petition (Lee et al., thereby offering significant benefits to recent-onset patients in 2014). Despite these and other efforts throughout the social and vocational aspects. Psychosocial therapies should A-P region to reduce the stigma associated with be implemented early to prevent deterioration of psychosocial schizophrenia, patients and families continue to be and cognitive functions. stigmatized and discriminated against.

The 97 FEP patients surveyed as part of the Italian Theme 8: Substance abuse in recent-onset Psychosis Incident Cohort Outcome Study reported psychosis impacts negatively on outcomes and experiencing discrimination in several key life areas; needs to be addressed in relationships with family members (43%), making Relative to the general population, individuals with friends (32%), relationships with neighbors (25%), severe psychotic disorders have increased risks for keeping a job (25%), finding a job (24%), and inti- smoking (odds ratio [OR] 4.6, 95% confidence CI mate relationships (23%) (Lasalvia et al., 2014). 4.3–4.9), heavy alcohol use (OR 4.0, 95% CI 3.6–4.4), Patients’ awareness of the negative consequences of heavy cannabis use (OR 3.5, 95% CI 3.2–3.7), and symptoms and disabilities led them to perceive dis- recreational drug use (OR 4.6, 95% CI 4.3–5.0) (Hartz crimination more easily and anticipated discrimina- et al., 2014). Around half of patients have a lifetime tion further limited their access to life opportunities; diagnosis of comorbid substance abuse (Buckley 37% had stopped seeking a close relationship and et al., 2009). Patients with comorbid substance abuse 34% had stopped looking for work, 58% felt the need have more positive symptoms, a greater risk of to conceal their diagnosis, and 37% reported that relapse, heightened risk of violence and suicide, more other people avoided them (Lasalvia et al., 2014). medical comorbidities, and a greater propensity to Relatives may experience “stigma by association,” and antipsychotic-related side-effects (Buckley et al., this can be greater in relatives experiencing mental 2009). There are high rates of substance misuse in health problems of their own (Ostman and Kjellin, recent-onset psychosis. For example, in the Spanish 2002). Child and Adolescent First Episode Psychosis study, In a study of 441 patients in urban northern rates were: tobacco 30.9%, cannabis 29.1%, alcohol China, the majority sought nonmental health path- 21.8%, cocaine 8.2%, amphetamines 2.7%, lysergic ways first rather than contacting mental HCPs acid diethylamide (LSD) 1.8%, and opiates 0.9% directly. On average, each patient consulted 3.4 (Baeza et al., 2009), and persistent substance misuse is carers, and the vast majority first visited local tertiary associated with poor outcome in the first year after general hospitals (56.4%) or local secondary general presentation (Turkington et al., 2009). Cannabis, hospitals (24.8%) (Zhang et al., 2013b). Mental alcohol, and tobacco/nicotine are the most commonly health stigmatizing attitudes in Japan are stronger used substances in those at clinical high risk of devel- than in countries such as Taiwan or Australia, pos- oping psychosis, although there is limited evidence to sibly due to institutionalism, lack of national cam- suggest that increased rates of substance use may be paigns to tackle stigma, and/or society’s valuing of associated with transition to psychosis (Addington conformity in Japan (Ando et al., 2013). Stigma et al., 2014). toward patients with schizophrenia among the Greater doses of cannabis have been associated Malay community is strong, and individuals who with subsequent higher depression and anxiety have been exposed to patients with schizophrenia or (Barrowclough et al., 2015), and cannabis use may be neurotic illnesses tend to have better perceptions related to higher positive symptom scores for FEP toward schizophrenia than the general public (Razali patients (Baeza et al., 2009). Cannabis use is associated and Ismail, 2014). A survey of 133 Chinese patients with discontinuation of antipsychotic medication in with schizophrenia revealed that education level recent-onset psychosis (van Nimwegen-Campailla impacts on the perception of stigma (Ren et al., et al., 2010), and cannabis abusing FEP patients may 2014); therefore, more psychoeducation should be be making two crucial decisions during treatment: undertaken to improve patients’ knowledge about whether to reduce or cease consumption of cannabis, schizophrenia. and whether or not to continue to take medications As already highlighted in themes 1, 2, and 6, family (Faridi et al., 2012). members and carers play an important role in supporting Cocaine and ecstasy use is relatively uncommon patients with medication adherence and day-to-day in the A-P region, and cannabis use is below the global tasks. Stigma may prevent patients and family members average. But opioid and amphetamine-type stimulant seeking help during the early stages of the disease and use is common, and there is an emerging trend in the beyond. Efforts should be made to reduce stigmatizing use of ketamine, particularly in Hong Kong where use behavior within healthcare services and society as a whole increased from 9.8% of total drug users in 2000 to particularly in countries where there is strong stigma 37.6% in 2009 (Dargan and Wood, 2012). These dif- attached to mental illness. The socio-cultural context is ferences are reflected in the varied rates of substance important to take into account in discussions with family abuse seen in patients with recent-onset psychosis in members. the A-P region. For instance, among first-episode

treatment-naive patients with psychosis in Bangalore, quetiapine in particular may improve depressive Southern India, the rate of alcohol dependence was symptoms in FEP (Crespo-Facorro et al., 2013). 17.3% and cannabis dependence 3.6%; lifetime and Clozapine has established antisuicidal effects current use of cannabis was less than 6% (Chand (Kasckow et al., 2011; Meltzer, 2012), but it may take et al., 2014). Self-reported cannabis use among 3644 several months for this to become apparent, and a patients receiving treatment for schizophrenia or high dose may be required (Kasckow et al., 2011). The schizoaffective disorder at the Provincial General use of high doses is associated with a higher risk of Hospital, Ratnapura, Sri Lanka, over five years (2000– developing AEs (Kasckow et al., 2011); however, 2004) was less than 3%, and all cannabis users were many of clozapine’s side-effects can be detected, pre- men (Rodrigo et al., 2010). Nevertheless, there is vented, minimized, and treated (Meltzer, 2012). For within-country variation, with an 11-year study of example, when one considers the hematological AEs, psychiatric comorbidity in patients with substance it is estimated that one in 10,000 people treated with abuse disorders attending an addiction treatment clozapine will die from agranulocytosis. Among center in Northern India reporting that inhalant and patients at high risk of suicide, approximately one in cannabis use was more likely to be found with psy- 10–20 will die from suicide. Thus, the relative risk chotic disorders and that 71.5% of patients with a favors clozapine when comparing only the suicide risk psychotic disorder had more than one substance abuse with risk from agranulocytosis (Kasckow et al., 2011). disorder (Basu et al., 2013). The reduced suicide risk in most patients also out- There is some evidence that dual diagnosis weighs the low risk (0.015–0.188%) of a serious patients might have a better outcome when prescribed adverse cardiac event (Merrill et al., 2005). clozapine, with less relapse into abuse of drugs or Psychiatric comorbidities such as depression and anxiety alcohol (Buckley et al., 2009). Identification and treat- disorders can have a negative impact on outcomes. We rec- ment of substance misuse should be a key component ommend that psychiatric comorbidities be given high priority of early intervention services with implications for during treatment planning in the context of the socioeconomic staff training and structure of services (Turkington and cultural background. et al., 2009). Comorbid substance abuse can worsen symptoms and outcomes and is a growing problem in the A-P region, despite Theme 10: Medical comorbidities are common and should be monitored and addressed the variability in the rates and types of substances abused. fastidiously in recent-onset psychosis The negative contribution that illicit drugs and alcohol make to the course of the illness, not least the legal complications, Patients diagnosed with schizophrenia have an including a heightened risk of incarceration, should be increased mortality rate compared with the general emphasized early in the treatment pathway. Patients should population (hazard ratio 2.05, 95% CI 2.01–2.09); be offered interventions that address comorbid substance around two thirds of this excess is associated abuse in a culturally sensitive manner. with increased rates of cardiovascular risk factors, including obesity, smoking, diabetes, hypertension, and dyslipidemia (Nielsen et al., 2013). All SGAs are Theme 9: Psychiatric comorbidities are common associated with weight gain compared with placebo and should be addressed in recent-onset treatment, although some (e.g. olanzapine, clozapine, psychosis and quetiapine) are more problematic than others Psychiatric comorbidities are common among patients (e.g. ziprasidone and aripiprazole) (Das et al., 2012); with schizophrenia at all phases of the illness. There is however, non-pharmacological factors also contribute an estimated prevalence of 15% for panic disorder, to obesity development in schizophrenia (Megna et al., 29% for post-traumatic stress disorder (PTSD), and 2011). Diet, exercise and CBT, alone or in combina- 23% for obsessive–compulsive disorder. Comorbid tion, can improve physical health and reduce body panic and PTSD symptoms may be associated with weight in patients with schizophrenia (Das et al., 2012; more severe psychopathology, as well as increased Hjorth et al., 2014). risks of suicidal ideation and behavior (Buckley et al., There is a significantly lower cardiovascular risk in 2009). Panic symptoms may also increase vulnerabil- early schizophrenia than in chronic schizophrenia, ity to comorbid substance use (Buckley et al., 2009). It and both diabetes and prediabetes appear uncommon is estimated that comorbid depression occurs in 50% in the early stages, especially in never-medicated of patients and is associated with a heightened risk (NM) patients (Mitchell et al., 2013). Meta-analysis of relapse (Buckley et al., 2009). Aripiprazole and shows that in both NM and FE patients, the overall

rate of metabolic syndrome (MetS) using standardized Among the 10 themes, several common prin- criteria is approximately 10% compared with 30–40% ciples emerge: adherence to antipsychotic medica- in medicated patients not in their first episode tions is crucial; substance abuse, psychiatric and (Mitchell et al., 2013). Rates of MetS are high among medical comorbidities can and should be addressed; medicated patients in Malaysia (46.7%), and those psychosocial interventions play a pivotal role with MetS have a greater cardiovascular risk (Said in each of these areas; and family members can et al., 2012). At least 40% of patients in South Korea play a vital role in overall patient care. The applica- exhibit MetS, with the greatest prevalence associated tion of the 10 themes and recommendations with the use of a combination of SGAs (Ko et al., discussed in this expert consensus should help to 2013). Elsewhere, the rate of MetS among medicated raise awareness of the specific issues involved patients has been estimated to be 46.0% in Singapore in the care of recent-onset psychosis patients (Lee et al., 2012), 27.5% in Japan (Sugawara et al., regardless of their socioeconomic and cultural 2010), 20.0% in Thailand (Srisurapanont et al., 2007), backgrounds. and 44–45% in India (Grover et al., 2012). Psychiatrists should be conscious of the physical conditions and metabolic issues associated with the use of Limitations antipsychotic drugs and the potential for antipsychotic The A-P region is extremely diverse with different therapies to worsen existing conditions such as diabetes health care systems, levels of socioeconomic develop- and compromised lipid metabolism. Strategies to improve ment and cultural attitudes, and we recognize that it is health and well-being should be promoted early on and not possible to provide the same level of treatment all patients should be screened regularly for metabolic throughout the region. We therefore focused primar- abnormalities. ily on general principles of care as a full analysis of treatment strategies within each country in the A-P region was beyond the scope of this article. These Conclusions recommendations should not be viewed as a comprehensive guide for treating schizophrenia. Our initial Antipsychotics are effective in treating acute psychotic literature search was limited to articles published in symptoms, particularly in patients with a recent onset the English language only however, non-English of psychosis. However, in many cases outcomes articles were included after the initial review stage if remain far from satisfactory. Providing optimal care to appropriate. recent-onset psychosis patients can improve these outcomes and not only benefits the patient, but their families, friends, and society as a whole. The impor- Acknowledgments tance of optimal care in recent-onset psychosis is well established, but clinical practice has yet to incorporate Medical writing support was provided by Huntsworth many of the more recent developments and there is a Health Singapore Ltd., funded by Janssen Asia-Pacific. lack of consistency of approach across the A-P region. Janssen Asia-Pacific provided logistical support during We therefore developed a set of principles for clini- the initial stages of this project. The authors have cians across the region to use on a day-to-day basis not received any honoraria or payment to participate in this project and the views expressed here are theirs throughout the patient journey. For instance, these alone. principles could form the basis of a checklist of items Janssen Asia-Pacific did not have a role in study to be discussed with patients and family members design; in the analysis, and interpretation of data; in the during initial consultations and at follow-up appoint- writing of the manuscript; and in the decision to submit ments. These issues are dynamic and change over the manuscript for publication. time. For instance, themes 1 and 2 are relevant for TLL, RE, JO, and DC contributed to the literature initial consultations, whereas substance abuse (theme search, study design, data analysis, and interpretation, 8), psychiatric (theme 9), and medical (theme 10) manuscript development, and review. MW, YH, TS, SK, comorbidities will need to be revisited frequently. MT, NA, AH, TB, CL, YKY, and RK contributed to the HCPs will need to review and reprioritize the issues at study design, data analysis and interpretation, manu- different stages of recovery, and adjust interventions script development and review. appropriately. These principles could also be inte- The authors would like to thank Nakao Iwata for grated into the initial training of junior HCPs and contributing to initial discussions during the early stages patient support group members. of the project.

Disclosures Squibb, Pfizer, Lundbeck, AstraZeneca, Hospira; travel support and honoraria for talks and consultancy TLL, TS, KS, MT, CL and RK have received honoraria from Eli Lilly, Bristol-Myers Squibb, AstraZeneca, for talks and consultancy from Janssen. Lundbeck, Janssen Cilag, Pfizer, Organon, Sanofi- MW has received honoraria for talks and Aventis, Wyeth, Hospira, Servier; and is a current or consultancy from Janssen and Lundbeck. past advisory board member for Lundbeck, Pfizer, YH has received honoraria for talks and AstraZeneca, and Roche. consultancy from Janssen and Lundbeck; and is a current or past advisory board member for Janssen and Pfizer. References NA has received honoraria for talks and Addington J., Case N., Saleem M.M., et al. (2014) consultancy from Janssen; and is a current or past Substance use in clinical high risk for psychosis: a advisory board member for Lundbeck. review of the literature. Early Interv Psychiatry. 8, AH has received grant monies for research from 104–112. Lundbeck; honoraria for talks and consultancy from Alvarez-Jiménez M., Gleeson J.F., Cotton S., et al. Janssen, Lundbeck, Eli Lilly, and Servier Pharmaceu- (2009) Predictors of adherence to cognitive- tical; has been involved in designing and participating behavioural therapy in first-episode psychosis. Can J in clinical trials organized by Janssen, Lundbeck, Psychiatry. 54, 710–718. Dainippon Sumitomo, and Servier Pharmaceutical; and is a current or past advisory board member for Alvarez-Jimenez M., Priede A., Hetrick S.E., et al. (2012) Risk factors for relapse following treatment Mitsubishi Tanabe Pharmaceutical. for first episode psychosis: a systematic review and TB has received grant monies for research from meta-analysis of longitudinal studies. Schizophr Res. Johnson and Johnson, and is a current or past advi- 139, 116–128. sory board member for Johnson and Johnson. RE has received grant monies for research clinical Ando S., Yamaguchi S., Aoki Y., Thornicroft G. (2013) trials from Janssen; honoraria for talks and Review of mental-health-related stigma in Japan. Psychiatry Clin Neurosci. 67, 471–482. consultancy from Janssen, Lundbeck, Otsuka, AstraZeneca, and Servier; and is a current or past Andreasen N.C., Carpenter W.T., Kane J.M., et al. advisory board member for Janssen, Lundbeck, (2005) Remission in schizophrenia: proposed criteria Otsuka, and Servier. and rationale for consensus. Am J Psychiatry. 162, JO has received grant monies for research, hono- 441–449. raria, and travel support for talks and consultancy Andreasen N.C., Liu D., Ziebell S., Vora A., Ho B.-C. from Janssen-Cilag, Lilly, AstraZeneca, Pfizer, (2013) Relapse duration, treatment intensity, and Lundbeck Glaxo, Novartis, and Bristol-Myers Squibb; brain tissue loss in schizophrenia: a prospective has been involved in designing and participating in longitudinal MRI study. Am J Psychiatry. 170, clinical trials for Janssen-Cilag, Lilly, AstraZeneca, 609–615. Pfizer, Lundbeck, Glaxo and Bristol-Myers Squibb; APA (2004) Practice guideline for the treatment of and is a current or past advisory board member for patients with schizophrenia. [Cited 18 November Janssen-Cilag, Lilly, AstraZeneca and Bristol-Myers 2015.] Available from URL: http://psychiatryonline Squibb. .org/pb/assets/raw/sitewide/practice_guidelines/ YKY has received grant monies for research from guidelines/schizophrenia.pdf GlaxoSmithKline, Eli Lilly, Pfizer, Janssen-Cilag (J&J), Armijo J., Méndez E., Morales R., et al. (2013) Efficacy Sanofi-Aventis, Wyeth, Otsuka, Astellas, Dai Nippon of community treatments for schizophrenia and Sumitomo, Atomic Energy Council, Lundbeck, and other psychotic disorders: a literature review. Front Roche; honoraria for talks and consultancy from Psychiatry. 4, 116. AstraZeneca, GlaxoSmithKline, Eli Lilly, Pfizer, Ascher-Svanum H., Faries D.E., Zhu B., et al. (2006) Janssen-Cilag (J&J), Wyeth, Otsuka, Fujisawa Medication adherence and long-term functional (Astellas), Sanofi-Aventis, Organon (Schering- outcomes in the treatment of schizophrenia in usual Plough) and Servier; and is a current or past advisory care. J Clin Psychiatry. 67, 453–460. board member for Janssen-Cilag (J&J), Pfizer, Eli Lilly Austin S.F., Mors O., Secher R.G., et al. (2013) and Lundbeck. Predictors of recovery in first episode psychosis: the DC has received grant monies for research from OPUS cohort at 10 year follow-up. Schizophr Res. Eli Lilly, Janssen Cilag, Roche, Allergen, Bristol-Myers 150, 163–168.

Awad A.G., Voruganti L.N.P. (2008) The burden of Chand P., Thirthalli J., Murthy P. (2014) Substance use schizophrenia on caregivers: a review. disorders among treatment naïve first-episode Pharmacoeconomics. 26, 149–162. psychosis patients. Compr Psychiatry. 55, 165–169. Bachmann S., Bottmer C., Schroder J. (2008) One-year Chen E.Y., Tang J.Y., Chan S.K., et al. (2012) Three-year outcome and its prediction in first-episode outcome of phase-specific early intervention for schizophrenia – a naturalistic study. first-episode psychosis: a cohort study in Hong Kong. Psychopathology. 41, 115–123. Hong Kong Med J. 18(Suppl 6), S7–S13. Baeza I., Graell M., Moreno D., et al. (2009) Cannabis Chen M., Wu G., Wang Z., et al. (2014) Two-year use in children and adolescents with first episode prospective case-controlled study of a case psychosis: influence on psychopathology and management program for community-dwelling short-term outcome (CAFEPS study). Schizophr Res. individuals with schizophrenia. Shanghai Arch 113, 129–137. Psychiatry. 26, 119–128. Barrowclough C., Gregg L., Lobban F., Bucci S., Emsley Chien W.T., Chan S.W.C. (2013) The effectiveness of R. (2015) The impact of cannabis use on clinical mutual support group intervention for Chinese outcomes in recent onset psychosis. Schizophr Bull. families of people with schizophrenia: a randomised 41, 382–390. controlled trial with 24-month follow-up. Int J Nurs Basu D., Sarkar S., Mattoo S.K. (2013) Psychiatric Stud. 50, 1326–1340. comorbidity in patients with substance use disorders Chien W.T., Thompson D.R. (2013) An RCT with attending an addiction treatment center in India over three-year follow-up of peer support groups for 11 years: case for a specialized “dual diagnosis Chinese families of persons with schizophrenia. clinic”. J Dual Diagn. 9, 23–29. Psychiatr Serv. 64, 997–1005. Bechdolf A., Wagner M., Veith V., et al. (2007) Chien W.T., Wong K.F. (2007) A family Randomized controlled multicentre trial of cognitive psychoeducation group program for Chinese people behaviour therapy in the early initial prodromal with schizophrenia in Hong Kong. Psychiatr Serv. 58, state: effects on social adjustment post treatment. 1003–1006. Early Interv Psychiatry. 1, 71–78. Chong M.-Y., Tan C.H., Fujii S., et al. (2004) Boardman G., McCann T., Kerr D. (2014) A peer Antipsychotic drug prescription for schizophrenia in support programme for enhancing adherence to oral East Asia: rationale for change. Psychiatry Clin antipsychotic medication in consumers with Neurosci. 58, 61–67. schizophrenia. J Adv Nurs. 70, 2293–2302. Chung K.F., Chan J.H. (2004) Can a less pejorative Bodén R., Brandt L., Kieler H., Andersen M., Reutfors Chinese translation for schizophrenia reduce stigma? J. (2011) Early non-adherence to medication and A study of adolescents’ attitudes toward people with other risk factors for rehospitalization in schizophrenia. Psychiatry Clin Neurosci. 58, schizophrenia and schizoaffective disorder. Schizophr 507–515. Res. 133, 36–41. Citrome L. (2014) Unmet needs in the treatment of Bradley G.M., Couchman G.M., Perlesz A., et al. (2006) schizophrenia: new targets to help different symptom Multiple-family group treatment for English- and domains. J Clin Psychiatry. 75(Suppl 1), 21–26. Vietnamese-speaking families living with Coldham E.L., Addington J., Addington D. (2002) schizophrenia. Psychiatr Serv. 57, 521–530. Medication adherence of individuals with a first Buckley P.F., Miller B.J., Lehrer D.S., Castle D.J. (2009) episode of psychosis. Acta Psychiatr Scand. 106, Psychiatric comorbidities and schizophrenia. 286–290. Schizophr Bull. 35, 383–402. Crespo-Facorro B., Ortiz-García de la Foz V., Mata I., Caseiro O., Pérez-Iglesias R., Mata I., et al. (2012) et al. (2013) Aripiprazole, Ziprasidone and Quetiapine Predicting relapse after a first episode of in the treatment of first-episode nonaffective non-affective psychosis: a three-year follow-up study. psychosis: a 12-week randomized, flexible-dose, J Psychiatr Res. 46, 1099–1105. open-label trial. Schizophr Res. 147, 375–382. Chakrabarti S. (2011) Family interventions in Dargan P.I., Wood D.M. (2012) Recreational drug use schizophrenia: issues of relevance for Asian in the Asia Pacific region: improvement in our countries. World J Psychiatry. 1, 4–7. understanding of the problem through the UNODC Chan S.W. (2011) Global perspective of burden of programmes. J Med Toxicol. 8, 295–299. family caregivers for persons with schizophrenia. Das C., Mendez G., Jagasia S., Labbate L.A. (2012) Arch Psychiatr Nurs. 25, 339–349. Second-generation antipsychotic use in schizophrenia

and associated weight gain: a critical review and risperidone in first-episode schizophrenia. J Clin meta-analysis of behavioral and pharmacologic Psychopharmacol. 30, 600–606. treatments. Ann Clin Psychiatry. 24, 225–239. Gearing R.E., Mian I., Sholonsky A., et al. (2009) Dolder C.R., Lacro J.P., Leckband S., Jeste D.V. (2003) Developing a risk-model of time to first-relapse for Interventions to improve antipsychotic medication children and adolescents with a psychotic disorder. adherence: review of recent literature. J Clin J Nerv Ment Dis. 197, 6–14. Psychopharmacol. 23, 389–399. Glick I.D., Correll C.U., Altamura A.C., et al. (2011) Durmaz H., Okanlı A. (2014) Investigation of the effect Mid-term and long-term efficacy and effectiveness of of self-efficacy levels of caregiver family members of antipsychotic medications for schizophrenia: a the individuals with schizophrenia on burden of data-driven, personalized clinical approach. J Clin care. Arch Psychiatr Nurs. 28, 290–294. Psychiatry. 72, 1616–1627. Emsley R., Medori R., Koen L., et al. (2008) Long-acting Grover S., Aggarwal M., Dutt A., et al. (2012) injectable risperidone in the treatment of subjects Prevalence of metabolic syndrome in patients with with recent-onset psychosis: a preliminary study. schizophrenia in India. Psychiatry Res. 200, J Clin Psychopharmacol. 28, 210–213. 1035–1037. Emsley R., Oosthuizen P.P., Koen L., Niehaus D.J.H., Gutiérrez-Maldonado J., Caqueo-Urízar A., Kavanagh Martinez G. (2012) Symptom recurrence following D.J. (2005) Burden of care and general health in intermittent treatment in first-episode schizophrenia families of patients with schizophrenia. Soc successfully treated for 2 years: a 3-year open-label Psychiatry Psychiatr Epidemiol. 40, 899–904. clinical study. J Clin Psychiatry. 73, e541–e547. Hartz S.M., Pato C.N., Medeiros H., et al. (2014) Comorbidity of severe psychotic disorders with Emsley R., Chiliza B., Asmal L., Harvey B.H. (2013) measures of substance use. JAMA Psychiatry. 71, The nature of relapse in schizophrenia. BMC 248–254. Psychiatry. 13, 50. Hassan G.A.M., Taha G.R.A. (2011) Long term Fanning F., Foley S., Lawlor E., et al. (2012) Group functioning in early onset psychosis: two years cognitive behavioural therapy for first episode prospective follow-up study. Behav Brain Funct. 7, psychosis: who’s referred, who attends and who 28. completes it? Early Interv Psychiatry. 6, 432–441. Henry L.P., Amminger G.P., Harris M.G., et al. (2010) Faridi K., Joober R., Malla A. (2012) Medication The EPPIC follow-up study of first-episode psychosis: adherence mediates the impact of sustained cannabis longer-term clinical and functional outcome 7 years use on symptom levels in first-episode psychosis. after index admission. J Clin Psychiatry. 71, Schizophr Res. 141, 78–82. 716–728. Fervaha G., Foussias G., Agid O., Remington G. (2014) Hjorth P., Davidsen A.S., Kilian R., Skrubbeltrang C. Motivational and neurocognitive deficits are central (2014) A systematic review of controlled to the prediction of longitudinal functional outcome interventions to reduce overweight and obesity in in schizophrenia. Acta Psychiatr Scand. 130, people with schizophrenia. Acta Psychiatr Scand. 290–299. 130, 279–289. Fraguas D., Llorente C., Rapado-Castro M., et al. (2008) Hui C.L.-M., Tang J.Y.-M., Leung C.-M., et al. (2013) A Attitude toward antipsychotic medication as a 3-year retrospective cohort study of predictors of predictor of antipsychotic treatment discontinuation relapse in first-episode psychosis in Hong Kong. Aust in first-episode early-onset psychosis. Rev Psiquiatr N Z J Psychiatry. 47, 746–753. Salud Ment. 1, 10–17. Jorm A.F., Morgan A.J., Wright A. (2008) A Fraguas D., Del Rey-Mejías A., Moreno C., et al. (2014) comparison of clinician, youth, and parent beliefs Duration of untreated psychosis predicts functional about helpfulness of interventions for early and clinical outcome in children and adolescents psychosis. Psychiatr Serv. 59, 1115–1120. with first-episode psychosis: a 2-year longitudinal Kaewprom C., Curtis J., Deane F.P. (2011) Factors study. Schizophr Res. 152, 130–138. involved in recovery from schizophrenia: a Gaebel W., Riesbeck M. (2014) Are there clinically qualitative study of Thai mental health nurses. Nurs useful predictors and early warning signs for pending Health Sci. 13, 323–327. relapse? Schizophr Res. 152, 469–477. Kasckow J., Felmet K., Zisook S. (2011) Managing Gafoor R., Landau S., Craig T.K.J., et al. (2010) Esquire suicide risk in patients with schizophrenia. CNS trial: efficacy and adverse effects of quetiapine versus Drugs. 25, 129–143.

Killackey E., Jackson H.J., McGorry P.D. (2008) Lee Y.S., Park I.H., Park S.-C., Kim J.-J., Kwon J.S. Vocational intervention in first-episode psychosis: (2014) Johyeonbyung (attunement disorder): individual placement and support v. treatment as renaming mind splitting disorder as a way to reduce usual. Br J Psychiatry. 193, 114–120. stigma of patients with schizophrenia in Korea. Asian Kim B., Lee S.-H., Choi T.K., et al. (2008) Effectiveness J Psychiatr. 8, 118–120. of risperidone long-acting injection in first-episode Lehman A.F., Kreyenbuhl J., Buchanan R.W., et al. schizophrenia: in naturalistic setting. Prog (2004) The Schizophrenia Patient Outcomes Neuropsychopharmacol Biol Psychiatry. 32, Research Team (PORT): updated treatment 1231–1235. recommendations 2003. Schizophr Bull. 30, Kim B., Lee S.-H., Yang Y.K., Park J.-I., Chung Y.-C. 193–217. (2012) Long-acting injectable antipsychotics for Lincoln T.M., Wilhelm K., Nestoriuc Y. (2007) first-episode schizophrenia: the pros and cons. Effectiveness of psychoeducation for relapse, Schizophr Res Treatment. 2012, 560836. symptoms, knowledge, adherence and functioning in Kim S.-W., Lee Y.-H., Jang J.-E., et al. (2013) psychotic disorders: a meta-analysis. Schizophr Res. Comparison of attitudes toward long-acting injectable 96, 232–245. antipsychotics among psychiatrists and patients. Int Lindenmayer J.-P., Liu-Seifert H., Kulkarni P.M., et al. Clin Psychopharmacol. 28, 80–86. (2009) Medication nonadherence and treatment Kin Wong K., Chiu R., Tang B., et al. (2008) A outcome in patients with schizophrenia or randomized controlled trial of a supported schizoaffective disorder with suboptimal prior employment program for persons with long-term response. J Clin Psychiatry. 70, 990–996. mental illness in Hong Kong. Psychiatr Serv. 59, Llorca P.M., Abbar M., Courtet P., et al. (2013) 84–90. Guidelines for the use and management of Kishimoto T., Agarwal V., Kishi T., et al. (2013a) Relapse long-acting injectable antipsychotics in serious prevention in schizophrenia: a systematic review and mental illness. BMC Psychiatry. 13, 340. meta-analysis of second-generation antipsychotics Malla A., Tibbo P., Chue P., et al. (2013) Long-acting versus first-generation antipsychotics. Mol injectable antipsychotics: recommendations for Psychiatry. 18, 53–66. clinicians. Can J Psychiatry. 58, 30S–35S. Kishimoto T., Watanabe K., Uchida H., et al. (2013b) Megna J.L., Schwartz T.L., Siddiqui U.A., Herrera Rojas Antipsychotic polypharmacy: a Japanese survey of M. (2011) Obesity in adults with serious and prescribers’ attitudes and rationales. Psychiatry Res. persistent mental illness: a review of postulated 209, 406–411. mechanisms and current interventions. Ann Clin Ko Y.-K., Soh M.-A., Kang S.-H., Lee J.-I. (2013) The Psychiatry. 23, 131–140. prevalence of metabolic syndrome in schizophrenic Meltzer H.Y. (2012) Clozapine: balancing safety with patients using antipsychotics. Clin Psychopharmacol superior antipsychotic efficacy. Clin Schizophr Relat Neurosci. 11, 80–88. Psychoses. 6, 134–144. Lambert M., Conus P., Cotton S., et al. (2010) Menezes N.M., Malla A.M., Norman R.M., et al. (2009) Prevalence, predictors, and consequences of A multi-site Canadian perspective: examining the long-term refusal of antipsychotic treatment in functional outcome from first-episode psychosis. Acta first-episode psychosis. J Clin Psychopharmacol. 30, Psychiatr Scand. 120, 138–146. 565–572. Merrill D.B., Dec G.W., Goff D.C. (2005) Adverse Lasalvia A., Zoppei S., Bonetto C., et al. (2014) The role cardiac effects associated with clozapine. J Clin of experienced and anticipated discrimination in the Psychopharmacol. 25, 32–41. lives of people with first-episode psychosis. Psychiatr Mitchell A.J., Vancampfort D., De Herdt A., Yu W., Serv. 65, 1034–1040. De Hert M. (2013) Is the prevalence of metabolic Lecomte T., Spidel A., Leclerc C., et al. (2008) Predictors syndrome and metabolic abnormalities increased in and profiles of treatment non-adherence and early schizophrenia? A comparative meta-analysis of engagement in services problems in early psychosis. first episode, untreated and treated patients. Schizophr Res. 102, 295–302. Schizophr Bull. 39, 295–305. Lee J., Nurjono M., Wong A., Salim A. (2012) Montreuil T.C., Cassidy C.M., Rabinovitch M., et al. Prevalence of metabolic syndrome among patients (2012) Case manager- and patient-rated alliance as a with schizophrenia in Singapore. Ann Acad Med predictor of medication adherence in first-episode Singap. 41, 457–462. psychosis. J Clin Psychopharmacol. 32, 465–469.

Morgan C., Lappin J., Heslin M., et al. (2014) insurance review & assessment service-national Reappraising the long-term course and outcome of patient sample. J Korean Med Sci. 29, 719–728. psychotic disorders: the AESOP-10 study. Psychol Perkins D.O., Gu H., Weiden P.J., et al. (2008) Med. 44, 2713–2726. Predictors of treatment discontinuation and Mueser K.T., McGurk S.R. (2014) Supported medication nonadherence in patients recovering employment for persons with serious mental illness: from a first episode of schizophrenia, current status and future directions. Encephale. schizophreniform disorder, or schizoaffective 40(Suppl 2), S45–S56. disorder: a randomized, double-blind, flexible-dose, multicenter study. J Clin Psychiatry. 69, 106–113. Naeem F., Saeed S., Irfan M., et al. (2015) Brief Rabinowitz J., Levine S.Z., Häfner H. (2006) A culturally adapted CBT for psychosis (CaCBTp): a population based elaboration of the role of age of randomized controlled trial from a low income onset on the course of schizophrenia. Schizophr Res. country. Schizophr Res. 164, 143–148. 88, 96–101. Nielsen R.E., Uggerby A.S., Jensen S.O.W., McGrath J.J. Razali S.M., Ismail Z. (2014) Public stigma towards (2013) Increasing mortality gap for patients patients with schizophrenia of ethnic Malay: a diagnosed with schizophrenia over the last three comparison between the general public and patients’ decades – a Danish nationwide study from 1980 to relatives. J Ment Health. 23, 176–180. 2010. Schizophr Res. 146, 22–27. Remington G., Agid O., Foussias G., et al. (2013) van Nimwegen-Campailla L., van Beveren N., Laan W., Clozapine’s role in the treatment of first-episode et al. (2010) Effect of early dysphoric response and schizophrenia. Am J Psychiatry. 170, 146–151. cannabis use on discontinuation of olanzapine or Ren Z., Wang H., Feng B., et al. (2014) A cross-sectional risperidone in patients with early psychosis. study on perception of stigma by Chinese Pharmacopsychiatry. 43, 281. schizophrenia patients. Neuropsychiatr Dis Treat. 10, NICE (2014) Psychosis and schizophrenia in adults: 535–540. treatment and management. [Cited 18 November Rizos E.N., Michalopoulou P.G., Siafakas N., et al. 2015.] Available from URL: http://www.nice.org (2010) Association of serum brain-derived .uk/Guidance/CG178 neurotrophic factor and duration of untreated Noguera A., Ballesta P., Baeza I., et al. (2013) psychosis in first-episode patients with schizophrenia. Twenty-four months of antipsychotic treatment in Neuropsychobiology. 62, 87–90. children and adolescents with first psychotic episode: Rodrigo C., Welgama S., Gunawardana A., et al. (2010) discontinuation and tolerability. J Clin A retrospective analysis of cannabis use in a cohort Psychopharmacol. 33, 463–471. of mentally ill patients in Sri Lanka and its Novick D., Haro J.M., Suarez D., et al. (2010) Predictors implications on policy development. Subst Abuse and clinical consequences of non-adherence with Treat Prev Policy. 5, 16. antipsychotic medication in the outpatient treatment Said M.A., Sulaiman A.H., Habil M.H., et al. (2012) of schizophrenia. Psychiatry Res. 176, 109–113. Metabolic syndrome and cardiovascular risk among patients with schizophrenia receiving antipsychotics Olivares J.M., Alptekin K., Azorin J.-M., et al. (2013) in Malaysia. Singapore Med J. 53, 801–807. Psychiatrists’ awareness of adherence to San L., Arranz B., Perez V., et al. (2012) One-year, antipsychotic medication in patients with randomized, open trial comparing olanzapine, schizophrenia: results from a survey conducted quetiapine, risperidone and ziprasidone effectiveness across Europe, the Middle East, and Africa. Patient in antipsychotic-naive patients with a first-episode Prefer Adherence. 7, 121–132. psychosis. Psychiatry Res. 200, 693–701. Opjordsmoen S., Friis S., Melle I., et al. (2010) A 2-year Sanz-Fuentenebro J., Taboada D., Palomo T., et al. follow-up of involuntary admission’s influence upon (2013) Randomized trial of clozapine vs. risperidone adherence and outcome in first-episode psychosis. in treatment-naïve first-episode schizophrenia: Acta Psychiatr Scand. 121, 371–376. results after one year. Schizophr Res. 149, 156–161. Ostman M., Kjellin L. (2002) Stigma by association: Sartorius N., Chiu H., Heok K.E., et al. (2014) Name psychological factors in relatives of people with change for schizophrenia. Schizophr Bull. 40, mental illness. Br J Psychiatry. 181, 494–498. 255–258. Park S.-C., Lee M.-S., Kang S.-G., Lee S.-H. (2014) Sato M. (2008) Influence of the Japanese name change Patterns of antipsychotic prescription to patients with for schizophrenia]. Seishin Shinkeigaku Zasshi. 110, schizophrenia in Korea: results from the health 849–854.

Sato S., Iwata K., Furukawa S.-I., et al. (2013) The Tan C.-H., Shinfuku N., Sim K. (2008) Psychotropic effects of the combination of cognitive training and prescription practices in East Asia: looking back and supported employment on improving clinical and peering ahead. Curr Opin Psychiatry. 21, 645–650. working outcomes for people with schizophrenia in Tang J.Y.-M., Chang W.-C., Hui C.L.-M., et al. (2014) Japan. Clin Pract Epidemiol Ment Health. 10, 18–27. Prospective relationship between duration of Schimmelmann B.G., Mehler-Wex C., Lambert M., et al. untreated psychosis and 13-year clinical outcome: a (2007) A prospective 12-week study of quetiapine in first-episode psychosis study. Schizophr Res. 153, adolescents with schizophrenia spectrum disorders. J 1–8. Child Adolesc Psychopharmacol. 17, 768–778. Taylor M., Ng K.Y.B. (2013) Should long-acting (depot) Selvendra A., Baetens D., Trauer T., Petrakis M., Castle antipsychotics be used in early schizophrenia? A D. (2014) First episode psychosis in an adult area systematic review. AustNZJPsychiatry. 47, mental health service-a closer look at early and 624–630. late-onset first episode psychosis. Australas Tharani A.J., Farooq S., Saleem F., Naveed A. (2013) Psychiatry. 22, 235–241. Compliance to antipsychotic medication: a challenge Shinfuku N., Tan C.-H. (2008) Pharmacotherapy for for client, family and health care providers. J Pak schizophrenic inpatients in East Asia – changes and Med Assoc. 63, 516–518. challenges. Int Rev Psychiatry. 20, 460–468. Tiihonen J., Haukka J., Taylor M., et al. (2011) A Shoib S., Mushtaq R., Dar M., et al. (2014) Psychosocial nationwide cohort study of oral and depot and medical factors affecting treatment compliance in antipsychotics after first hospitalization for patients attending psychiatric hospital: a study from schizophrenia. Am J Psychiatry. 168, 603–609. Kashmir. Int J Basic Clin Pharmacol. 3, 220. Tse S., Davidson L., Chung K., Ng K.L., Yu C.H. (2014) Shrivastava A., Johnston M., Terpstra K., Stitt L., Shah Differences and similarities between functional and N. (2012) Atypical antipsychotics usage in long-term personal recovery in an Asian population: a cluster follow-up of first episode schizophrenia. Indian J analytic approach. Psychiatry. 77, 41–56. Psychiatry. 54, 248–252. Tunis S.L., Faries D.E., Stensland M.D., Hay D.P., Kinon Sim K., Su A., Ungvari G.S., et al. (2004) Depot B.J. (2007) An examination of factors affecting antipsychotic use in schizophrenia: an East Asian persistence with initial antipsychotic treatment in perspective. Hum Psychopharmacol. 19, 103–109. patients with schizophrenia. Curr Med Res Opin. 23, Siu B.W.M., Ng B.F.L., Li V.C.K., et al. (2012) Mental 97–104. health recovery for psychiatric inpatient services: Turkington A., Mulholland C.C., Rushe T.M., et al. perceived importance of the elements of recovery. (2009) Impact of persistent substance misuse on East Asian Arch Psychiatry. 22, 39–48. 1-year outcome in first-episode psychosis. Br J Srisurapanont M., Likhitsathian S., Boonyanaruthee V., Psychiatry. 195, 242–248. Charnsilp C., Jarusuraisin N. (2007) Metabolic Uzenoff S.R., Perkins D.O., Hamer R.M., Wiesen C.A., syndrome in Thai schizophrenic patients: a Penn D.L. (2008) A preliminary trial of naturalistic one-year follow-up study. BMC adherence-coping-education (ACE) therapy for early Psychiatry. 7, 14. psychosis. J Nerv Ment Dis. 196, 572–575. Steger K.A., Cassidy C., Rabinovitch M., Joober R., Üçok A., Serbest S., Kandemir P.E. (2011) Remission Malla A. (2012) Impact of symptom resolution on after first-episode schizophrenia: results of a medication adherence in first episode psychosis. long-term follow-up. Psychiatry Res. 189, 33–37. Psychiatry Res. 196, 45–51. Verma S., Subramaniam M., Abdin E., Poon L.Y., Stewart K.D. (2013) Factors contributing to Chong S.A. (2012) Symptomatic and functional engagement during the initial stages of treatment for remission in patients with first-episode psychosis. psychosis. Qual Health Res. 23, 336–347. Acta Psychiatr Scand. 126, 282–289. Subotnik K.L., Nuechterlein K.H., Ventura J., et al. Viala A., Cornic F., Vacheron M.-N. (2012) Treatment (2011) Risperidone nonadherence and return of adherence with early prescription of long-acting positive symptoms in the early course of injectable antipsychotics in recent-onset schizophrenia. Am J Psychiatry. 168, 286–292. schizophrenia. Schizophr Res Treatment. 2012, Sugawara N., Yasui-Furukori N., Sato Y., et al. (2010) 368687. Prevalence of metabolic syndrome among patients Weiden P.J., Schooler N.R., Weedon J.C., et al. (2009) A with schizophrenia in Japan. Schizophr Res. 123, randomized controlled trial of long-acting injectable 244–250. risperidone vs continuation on oral atypical

antipsychotics for first-episode schizophrenia management of patients after first psychotic episode patients: initial adherence outcome. J Clin in 5-year follow-up. Psychiatr Danub. 22(Suppl 1), Psychiatry. 70, 1397–1406. S92–S94. Wunderink L., Nienhuis F.J., Sytema S., et al. (2007) Zhang J.-P., Gallego J.A., Robinson D.G., et al. (2013a) Guided discontinuation versus maintenance Efficacy and safety of individual second-generation treatment in remitted first-episode psychosis: relapse vs. first-generation antipsychotics in first-episode rates and functional outcome. J Clin Psychiatry. 68, psychosis: a systematic review and meta-analysis. Int 654–661. J Neuropsychopharmacol. 16, 1205–1218. Wunderink L., Nieboer R.M., Wiersma D., Sytema S., Zhang W., Li X., Lin Y., et al. (2013b) Pathways to Nienhuis F.J. (2013) Recovery in remitted psychiatric care in urban north China: a general first-episode psychosis at 7 years of follow-up of an hospital based study. Int J Ment Health Syst. 7, 22. early dose reduction/discontinuation or maintenance Ziermans T.B., Schothorst P.F., Schnack H.G., et al. treatment strategy: long-term follow-up of a 2-year (2012) Progressive structural brain changes during randomized clinical trial. JAMA Psychiatry. 70, development of psychosis. Schizophr Bull. 38, 913–920. 519–530. Yoon C.K., Aziz S.A. (2014) A review of schizophrenia Zipursky R.B., Menezes N.M., Streiner D.L. (2014) Risk research in Malaysia. Med J Malaysia. 69, 46–53. of symptom recurrence with medication Zaytseva Y., Gurovich I.Y., Shmukler A. (2010) discontinuation in first-episode psychosis: a Effectiveness of the integrated long-term program of systematic review. Schizophr Res. 152, 408–414.